Copper-mediated rapid and facile oxidative dehydrogenation of dihydrobenzocarbazoles

Article abstract of DOI:10.1080/00397911.2020.1731757

Rapid method for the oxidative dehydrogenation of dihydrobenzocarbazoles has been introduced by using bench scale and commercially available reagent; copper chloride, in excellent yield with easy workup. The scope of the reaction has been studied with broad range of substitutes.

Full text of DOI:10.1080/00397911.2020.1731757

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
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Copper-mediated rapid and facile oxidative
dehydrogenation of dihydrobenzocarbazoles
Vivek T. Humne & Avinash G. Ulhe
To cite this article: Vivek T. Humne & Avinash G. Ulhe (2020): Copper-mediated rapid and
facile oxidative dehydrogenation of dihydrobenzocarbazoles, Synthetic Communications, DOI:
10.1080/00397911.2020.1731757
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https://doi.org/10.1080/00397911.2020.1731757
Copper-mediated rapid and facile oxidative
dehydrogenation of dihydrobenzocarbazoles
Vivek T. Humne and Avinash G. Ulhe
Department of Chemistry, Shri R. R. Lahoti Science College, Morshi, India
ABSTRACT
ARTICLE HISTORY
Received 12 January 2020
Rapid method for the oxidative dehydrogenation of dihydrobenzo-
carbazoles has been introduced by using bench scale and commer-
cially available reagent; copper chloride, in excellent yield with easy
workup. The scope of the reaction has been studied with broad
range of substitutes
KEYWORDS
Benzocarbazole; copper
chloride; dehydrogenation;
heterocyclic compound
GRAPHICAL ABSTRACT
R1
N
R2
H
Benzocarbazole
CuCl2.2H2O
DMSO, 120°C
O
N
NH
hetero
hetero
R1
Pyridazi-3-one
Rapid process
Commercial reagent
High yield
Wide subsrate scope
R1
N
Me
Indole
Introduction
Dehydrogenation is an important process in organic synthesis for the industrial and
academic persistence. Myriad of work has been focused for the development of
dehydrogenation process, including metal-promoted process is known to be a key
step.[1] Over the last few decades, copper-mediated reactions such as cylication,[2a] oxi-
dation,[2b] coupling reaction[2c–g] and one-pot addition[2h] received considerable atten-
tion in organic synthesis. Moreover, copper (II) salt plays a significant role in organic
transformations. Literature survey revealed that Cu (II)/O2 in presence of chelex,[3a]
propyl framed-ligand[3b] and HPPDO[3c] used for oxidation. Additionally, (a) cylization:
Cu(II)/O2/TEMPO,[3d] (b) epoxidation: Cu(II)/O2 with aldehyde as co-oxidant or
CONTACT Vivek T. Humne
vivekhumne2013@gmail.com
Supplemental data for this article can be accessed on the publisher’s website
ß 2020 Taylor & Francis Group, LLC

2
V. T. HUMNE AND A. G. ULHE
norbornene,[3e] (c) addition reaction: Cu(II)/O2 in acidic condition,[3f] (d) coupling
reaction: Cu(II)/methanol, pyridine was successfully used.[3g] Copper chloride is become
a favorite choice owing to their inexpensive, nontoxic, environmentally benign charac-
teristics and insensitive to air as well as moisture. The main advantage is that it can be
easily removed from the reaction by aqueous workup. Additionally, copper chloride
gives a high degree of regioselectivity with less possibility of side products. However, lit-
erature survey shows that a very limited number of heterocyclic moieties undergo
dehydrogenation process by copper chloride while required extra additives and
oxidants.[4a–e]
Due to notable significance of benzo[a],[b],and[c]-carbazoles in material and bio-
logical activity, huge efforts have been made for their construction.[5] Various synthetic
approaches such as metal-catalyzed,[6a–e,6h–i] domino annulation of indoles,[6f] and tan-
dem cyclization/C ꢀ H functionalization of two different alkynes[6g] has been reported.
However, Fischer–Borsche synthesis is the most common practical method used for the
preparation of benzocarbazoles. In general, this involves the condensation of phenylhy-
drazine with a or b-tetralone, followed by aromatization. The final step, aromatization
of dihydrobenzo[a]carbazole, is the most challenging task. To the best of our know-
ledge, very few reagents are documented in the literature to afford aromatization pro-
cess. Following limitations have been observed in the aromatic process; (a) Pd/C is
often used with high boiling point solvent,[7a,b] (b) DDQ, an organic-derived reagent is
used,[7c,d] and (c) transition metal-based transformations are used for the preparation of
benzocarbazoles.[7e] However, these approaches required high temperature, loading
of stoichiometric amounts of catalyst, longer reaction time and low yield. To the best
of our knowledge, a very few reports are documented in the literature for the dehydro-
genation of dihydrobenzocarbazoles. Therefore, development of rapid, efficient and
conventional method for dehydrogenation of dihydrobenzocarbazoles is exceed-
ingly desirable.
Result and discussions
We started our experimental strategy by condensation of commercially available phenyl
hydrazine with tetralone which was readily converted into dihydrobenzo[a]carbazole.
Encouraged from our previous report based on the development of regioselective one-
pot dehydrogenation and iodination of dihydrobenzocarbazole using periodic acid in
PEG-400.[8] In this process, iodo-benzo[a]carbazole product was achieved by using two-
fold of periodic acid as a reagent. Recently, we developed copper-mediated organic
transformation for biological active scaffold.[9] Therefore, we thought commercially
available copper-source could be used for dehydrogenation of dihydrobenzocarbazoles.
Initially, when reaction was performed in the presence of CuCl, CuO and CuSO4 in
dimethyl sulphoxide (DMSO) at 100 ꢁC for 2 h, did not afford the desired product (Table 1,
entry a, b, c). Trace amount of product was observed by using Cu(OAc)2 while moderate
yield was obtained by CuBr2. Recently, Guo et al. exposed the copper (I)-catalyzed synthesis
of 2-arylquinolines under aerobic oxidative protocol.[10] To employ the similar reaction con-
dition (CuCl/O2 in DMSO at 120 ꢁC for 10h), desired product was obtained in moder-
ate yield.

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SYNTHETIC COMMUNICATIONSV
3
Table 1. Optimization condition.
Entry
Reagenta (eqv)
CuCl (2 eqv)c
Time (min)
Yieldb (%)
a
b
c
d
e
f
g
h
i
120
120
120
120
120
120
120
35
NR
NR
NR
trace
40d
20d
42d
81
CuO (2 eqv)
CuSO4.5H2O (2 eqv)
Cu(OAc)2 (2 eqv)
CuBr2 (2 eqv)
CuCl2.2H2O (0.1 eqv)c
CuCl2.2H2O (0.5 eqv)
CuCl2.2H2O (1 eqv)
CuCl2.2H2O (2 eqv)
CuCl2.2H2O (3 eqv)
10
10
89
88
j
aAll reagents have good solubility in DMSO.
bIsolated yield.
cReagent was used with O2.
dProduct was isolated with recovering of starting substrate.
Further, we optimized the reaction condition with copper chloride as reagent. On
increasing the mole% of copper chloride from 10 mol% to equimolar proportional
(Table 1, entry f–h), the yield was increases with moderate to good yield. Under the
oxygen atmosphere with 10 mol% CuCl2ꢂ2H2O in dimethyl sulphoxide at 120 ꢁC for 2 h,
no significant change of yield was observed. To increase the two-fold degree of the
CuCl2ꢂ2H2O afforded the desired dehydrogenated product in 10 min with good yield
(Table 1, entry i). Finally, attempts to increase the reaction temperature and propor-
tional of copper chloride does not affect the yield of the product.
To make the generality of this new method and check the versatility of copper-
catalyzed dehydrogenation, various substituents of dihydrobenzocarbazoles were suc-
cessful studied (Scheme 1, entry 3a–j). Notably, no effect of electron-donating and
electron-drawing substitutes were observed in oxidative dehydrogenation process.
Significantly, N-allyl group remains intact throughout the whole procedure
(Scheme 1, entry 3h). However, 3j could not supported the optimized condition.
This may be due to interactive property of copper chloride with nitro-functionality.
After exploring the reactivity pattern of various dihydrobenzo[a]carbazoles, we fur-
ther planned to explore the scope of this process to other N-heterocycles such as dihy-
dropyridazine-3-one and indoline. Dehydrogenation of 4a–f under optimized condition
proceeded smoothly, afforded product 5a–f in good yield. The reaction was neat and
clean (Scheme 2).
To study the insight of mechanism for copper-mediated oxidative dehydrogenation
process, we studied the formation of copper chloride-substrate 1 complex. In order to
understand the copper chloride-substrate 1 complex formation, we performed an
experiment in which copper chloride was thoroughly grid with substrate 1 from room
temperature to 100 ꢁC for 30 min. The progress of reaction was monitored by tlc and IR
spectra after the interval of 10 min (Fig. 1). The IR spectra A and B attributed that

4
V. T. HUMNE AND A. G. ULHE
Scheme 1. Rapid oxidative dehydrogenation of dihydrobenzocarbazole using copper chloride.
aReaction condition: Substrate 1 (2.2 mmol), CuCl2.2H2O (4.5 mmol) in DMSO at 120 ꢁC for 30 min.
bIsolated yield.
region 3431–3167 cmꢀ1 shows a broad band due to N-H streaching. Quagliano et al.
have found that formation of nitrogen to metal bond results in a broading of N–H
stretching frequency.[11] Clearly, this indicates that copper chloride first undergo the
process of complex formation with substrate 1 while the aliphatic region 2941 cmꢀ1
,
2883 cmꢀ1 and 2833 cmꢀ1 remain intact. However, the appearance of strong intense
band at 1595 cmꢀ1 and increase of aromatic C–H band from 3049 cmꢀ1 to 3051 cmꢀ1
resembles the progress of dehydrogenation process. The additional characteristic bands
are obtained at 1325 cmꢀ1, 1307 cmꢀ1, and 1280 cmꢀ1
.
On the other hand, we tested optimized reaction under aerobic and inert condition.
Molecular oxygen is an ultimate oxidant that has been attracted much attention from
the synthetic community.[12] To our delight, when oxygen gas was bubbled in reaction
mixture, the dehydrogenation process was accomplished in a short time (10 min). While

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SYNTHETIC COMMUNICATIONSV
5
Scheme 2. Rapid oxidative dehydrogenation of other heterocycles using copper chloride.
aReaction condition: Substrate 1 (2.2 mmol), CuCl2.2H2O (4.5 mmol) in DMSO at 120 ꢁC for 10 min.
bIsolated yield.
F
E
D
(30 min)
(20 min)
C
B
A
(10 min)
(rt)
4000 3500 3000 2500 2000 1500 1000
Wavenumber (cm-1)
500
Figure 1. FTIR Study of complex formation (A) substrate 1; (B) copper chloride/substrate 1 grinding
at rt; (C) copper chloride/substrate 1 grinding at 100 ꢁC for 10 min; (D) copper chloride/substrate 1
grinding at 100ꢁC for 20 min; (E) copper chloride/substrate 1 grinding at 100ꢁC for 30 min; (F)
Product 2.

6
V. T. HUMNE AND A. G. ULHE
Scheme 3. Plausible mechanism for aromatization of dihydrobenzo[a]carbazole.
Scheme 4. Utility of copper-mediated hydrogenation process for coupling reaction.
rate of reaction was slow under nitrogen and argon atmosphere. This study showed
molecular oxygen is the necessary condition for dehydrogenation process.
Based on these results, plausible reaction mechanism of oxidative dehydrogenation
process is outlined in Scheme 3. Copper (II) chloride preferably interact with substrate
1 in DMSO to give the complex A.[13,14] However, copper (II) chloride have good solu-
bility in DMSO. White et al.[15]explained the reactivity of series of copper (II) salt based
on its anion counterpart, leading to intermediate A. In the next step, elimination of
CuCl furnished intermediate B. Under the aerobic condition, CuCl could get converted
into CuCl(OH) (Scheme 3).[16] Finally, the intermediate B could isomerized to prod-
uct 2.
To foresee the utility of the present method, the requisite dehydrogenated product 3b
was treated with iodine in acetonitrile at 60 ꢁC. The Buchward coupling reaction with
benzyl protected iodo substituted benzo[a]carbazole (6) and aniline has been carried in
presence of Pd2(dba)2, Xanthphos, K2PO4, toluene at 100 ꢁC for 2 h. Similarly, Heck
coupling was performed with 6 and ethyl acrylate under Pd(OAc)2, triethylamine, tolu-
ene at 100 ꢁC for 4 h, afforded the corresponding product in 69% yield (Scheme 4). This
preparation could allow the development of various promising precursors for mater-
ial sciences.
Experimental
General procedure for the synthesis of benzocarbazole, pyridazine-3-one
and indole
In 50 ml round bottom flask, CuCl2ꢂ2H2O (4.5 mmol) thoroughly dissolved in 10 mL
DMSO. To this solution, dihydrobenzo[a]carbazole (2.2 mmol) was added and stirred

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SYNTHETIC COMMUNICATIONSV
7
for 30 min at room temperature. The resulting mixture was heated at 120 ꢁC through
open vessel. The progress of the reaction was monitored by TLC. After completion of
the reaction, the mixture was quenched by few drops of con. HCl and poured in ice
cold water. The product was isolated. Filter and recrystalized by methanol.
11H-benzo[a]carbazole (3a): Yield 91%, m.p.: 230–231 ꢁC, IR (ꢀ cmꢀ1): 3030, 1600,
1
1587; H NMR (300 MHz, CDCl3): d 8.13 (d, J ¼ 8.1 Hz, 1H), 8.01 (d, J ¼ 8.1 Hz, 1H),
7.62 (d, J ¼ 7.8 Hz, 1H), 7.45–7.28 (m, 7H), 4.28 (s, 3H); 13C NMR (100 MHz, CDCl3):
140.4, 136.5, 134.8, 133.5, 130.1, 125.5, 125.2, 123.9, 123.8, 121.1, 120.6, 120.1, 119.7,
118.9, 119.1, 111.0, 44.6; HRMS (ES) m/z ¼ 232.1004 calcd for C17H13N [M þ H]þ,
found 232.1007
Representative procedure for the 5-Iodo-11N-benzyl-benzo[a]carbazole (6)
In round bottom flask, 11 N-Benzyl-benzo[a]carbazole (0.912 mmol) and iodine
(1.368 mmol) in acetonitrile (5 mL) was stirred for 2 h at 60 ꢁC. The progress of the
reaction was checked by TLC. The workup of the reaction was carried out in ice cold
saturated sodium thiosulfate solution (20 mL). Extracted wih ethyl acetate and washed
with water followed by brine solution (50 mL ꢃ 2) and further purified by column
chromatography (ethyl acetate: pet-ether) to give the desired product.
1
Yield: 90%; m.p.: 156–160 ꢁC; IR (cmꢀ1): 3053, 1218; H NMR (400 MHz, DMSO-d6):
d 9.10 (s, 1H), 8.81 (d, J ¼ 1.6 Hz, 1H), 8.39 (d, J ¼ 8.4 Hz, 1H), 8.25 (d, J ¼ 8.4 Hz, 1H),
7.77 (t, J ¼ 6.8 Hz, 1H), 7.65–7.55 (m, 3H), 7.28–7.22 (m, 4H), 7.04 (d, J ¼ 6.8 Hz, 2H),
6.17 (s, 2H); 13C NMR (101 MHz, DMSO-d6): d 140.31, 137.79, 135.29, 134.05, 133.48,
132.70, 131.46, 129.37,129.37, 129.11, 127.79, 127.46, 127.13, 126.17, 126.17, 124.29,
123.42, 122.64, 119.88, 113.06, 90.18, 84.42, 49.22.
Representative procedure for the Buckward coupling (7)
A mixture of N-benzyl-iodo-benzo[a]carbazole (0.115 mmol), Pd2(dba)3 tri(dibenzylide-
neacetone)dipalladium (15 mol%), Xanthphos (30 mol%) and K3PO4 (0.168 mmol) in
dry toluene was added 4-methoxy aniline (0.138 mmol) under the flow of argon and
immediately seal the pressure tube. Reaction mixture was stirred at 80 ꢁC for 2 h. The
completion of the reaction was confirmed by TLC. The reaction mixture was extracted
by ethyl acetate and wash the organic layer with ammonium chloride and water.
Evaporate organic solvent under vacuum and purified by column chromatography using
ethyl aceate:hexane.
1
Yield: 79%; m.p.: 309–312 ꢁC; H NMR (400 MHz, DMSO-d6): d 8.48–8.38 (m, 1H),
8.30–8.24 (m, 1H), 8.17 (d, J ¼ 7.8 Hz, 1H), 8.09 (s, 1H), 7.70 (d, J ¼ 8.6 Hz, 2H),
7.52–7.38 (m, 3H), 7.34 ꢀ 7.18 (m, J ¼ 21.3, 7.1 Hz, 4H), 7.13 (d, J ¼ 7.3 Hz, 2H), 6.83
(q, J ¼ 9.1 Hz, 4H), 6.15 (s, 2H), 3.69 (s, 3H); 13C NMR (100 MHz, DMSO-d6): d 152.55,
141.43, 141.10, 138.35, 133.92, 131.44, 129.46, 129.43, 129.29, 127.63, 126.33, 126.14,
125.58, 125.11, 124.84, 122.98, 122.84, 120.14, 120.11, 119.21, 117.41, 115.12, 111.68,
110.22, 55.70, 49.13.

8
V. T. HUMNE AND A. G. ULHE
Representative procedure for the Heck coupling (8)
mixture of N-benzyl-iodo-benzo[a]carbazole (0.115 mmol), ethyl acrylate
A
(0.173 mmol), triphenyl phosphine (20 mol%), triethylamine Et3N (2 equiv), and palla-
dium acetate Pd(OAc)2 (5 mol%) in dimethyl formamide sealed in pressure tube under
argon atmosphere. Reaction mixture was stirred at 100 ꢁC temperature for 5 h. The
completion of the reaction was confirmed by TLC. The reaction mixture was extracted
by ethyl acetate and wash with ammonium chloride and water. Evaporate organic solv-
ent under vacuum and purified by column chromatography using ethyl aceate:hexane.
1
Yield: 81%; m.p.: 311–317 ꢁC; H NMR (400 MHz, DMSO-d6): d 8.94 (s, 1H), 8.56 (d,
J ¼ 15.6 Hz, 1H), 8.44 (d, J ¼ 8.0 Hz, 2H), 8.32 (d, J ¼ 8.2 Hz, 1H), 7.72 (d, J ¼ 8.3 Hz,
1H), 7.59 (t, 1H), 7.50 (t, J ¼ 7.7 Hz, 3H), 7.37 (t, J ¼ 7.4 Hz, 1H), 7.31 ꢀ 7.18 (m,
J ¼ 24.3, 7.1 Hz, 4H), 7.09 (d, J ¼ 7.5 Hz, 2H), 6.85 (d, J ¼ 15.6 Hz, 1H), 6.14 (s, 2H),
4.28 (q, J ¼ 7.1 Hz, 2H), 1.33 (t, J ¼ 7.1 Hz, 3H); 13C NMR (101 MHz, DMSO-d6): d
167.0, 142.1, 141.5, 137.9, 136.2, 131.3, 129.1, 127.6, 126.2, 126.2, 126.1, 124.5, 123.3,
123.2, 123.0, 121.9, 121.0, 120.6, 120.1, 119.1, 118.5, 110.5, 60.1, 49.2, 14.6.
Conclusion
In conclusion, we have developed a rapid and efficient protocol of dehydrogenation
process for variety of dihydrobenzocarbazole using copper chloride. Further, this
method is extended to different N-heterocylic compounds. The advantages of this
method are shorter reaction time, no column chromatography and have a wide sub-
strate scope with excellent yield. The present method is found to be expedient and ele-
gant. Further studies toward broadening the scope to include related heterocycles and
applications are underway.
Acknowledgements
VTH is thankful to the Department of Chemistry, Savitribai Phule Pune University for providing
characterization data and Shri. R. R. Lahoti Science College, Morshi, for providing neces-
sary facilities.
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